Estradiol (estra-1, 3, 5(10)-triene-3, 17.beta.-diol or 17.beta.-estradiol) is a pharmaceutical compound commonly administered in hormone replacement therapy regimens. The designation 17.alpha.-estradiol was incorrectly used prior to ca. 1952. (Estradiol by Eugene A. Salole in Analytical Profiles of Drug Substances, K.Florey, ed. (1986) Academic Press, Inc. 15:283-318). Estradiol is known to form several crystal structures. The most stable form of estradiol is estradiol hemihydrate (E2-HH). Two anhydrous structures have been reported in the literature. Estradiol also forms solvates with organic solvents such as methanol and ethanol.
A common method for characterizing estradiol crystalline forms is provided by X-ray powder diffraction data. Excluding solvates other than hydrates, there are three sets of x-ray powder diffraction (XRD) data for 17.beta.-estradiol published in the literature.
The XRD pattern for the most stable anhydrous crystal structure is provided in the Joint Committee on Powder Diffraction Standards (JCPDS) 38-1522. The sample was prepared by heating the hemihydrate at 170.degree. C. for several hours, presumably at ambient pressure.
The first set of data relating to E2-HH was collected by Parsons et al. (reference). JCPDS File 10-851 lists the same 30 diffraction peaks as Parsons, et al. with slightly different intensities. JCPDS describes 10-851 as alpha-E2-HH, Chemical Abstracts Service (CAS) registry number 50-28-2 possessing a molecular weight of 281.39 and a melting point of 176-179.degree. C. It is believed that the naming of the compound in this reference is incorrect in accordance with the practice at the time as discussed above. The second set of data for E2-HH is JCPDS File 10-549. This is listed as P-Estradiol (1, 3, 5(10)-estratriene-3, 17.beta.diol) with a CAS number of 50-28-2. This data is consistent with the description of E2-HH provided by Salole. The structure is orthorhombic with crystallographic parameters (measured in angstroms) of a=12.04, b=19.26, c=6.642, A=0.6251, C=3449 (orthorhombic), similar to values listed by Hospital (1972) of a=12.055.+-.0.003, b=19.280.+-.0.003, c=6.632.+-.0.002 (orthorhombic).
Resetarits, et al. (Int'. J. Pharma. (1979) 2:113-123) also made a crystal with a "relatively rapid recrystallization" process from absolute ethanol at 37.degree. C. The Raman spectrum and x-ray diffraction pattern were similar to that from the hemihydrate.
The present invention provides a stable crystalline form of estradiol distinguishable from the foregoing crystal structures of estradiol based on XRD data and having greater solubility and thermodynamic activity with respect to E2-HH suitable for incorporation into pharmaceutical formulations.